Cation-Chloride Cotransporters and Neuronal Function

Blaesse, Peter; Airaksinen, Matti S.; Rivera, Claudio; Kaila, Kai

doi:10.1016/j.neuron.2009.03.003

Cited by 715 publications

(811 citation statements)

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“…The driving force for the Cl − current that is necessary for hyperpolarizing IPSPs is generated by the K + -Cl − cotransporter KCC2, a neuron-specific cotransporter that extrudes Cl − under physiological conditions in adulthood (Farrant and Kaila, 2007;Blaesse et al, 2009). Accordingly, the change in GABA A receptor-mediated responses from depolarizing to hyperpolarizing seen during early neuronal development is coupled to the induction of the KCC2 expression (Rivera et al, 1999); these data thus support the view that KCC2 is the main Cl − extruder to promote fast hyperpolarizing postsynaptic inhibition in the brain.…”

Section: Gaba a Receptor-mediated Phasic Inhibitionmentioning

confidence: 99%

“…This view is supported by experimental evidence in which it was shown that following damage to afferents in the spinal cord, BDNF liberated by microglia activates trkB receptors leading to a KCC2 down-regulation and a depolarizing shift in GABAergic reversal potentials associated with pathological pain responses (Price et al, 2005;Lu et al, 2008). It has also been shown that experimentally induced interictal activity in hippocampal slices maintained in vitro, downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl − extrusion (Rivera et al, 2002(Rivera et al, , 2004Blaesse et al, 2009). Alterations in the balance of NKCC1 and KCC2 activity have also been identified in the subiculum and hippocampus of epileptic patients by Munoz et al (2007).…”

Section: Gaba a Receptor-mediated Inhibition May Implement Epileptifomentioning

confidence: 99%

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GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

224

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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Section: Gaba a Receptor-mediated Phasic Inhibitionmentioning

confidence: 99%

Section: Gaba a Receptor-mediated Inhibition May Implement Epileptifomentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

224

253

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“…The action of GABA depends on the concentration of intracellular Cl − ([Cl − ] i ): when the [Cl − ] i is high during embryonic development, GABA A R activation results in Cl − efflux, membrane depolarization, and excitatory synaptic transmission; whereas low [Cl − ] i results in Cl − influx, membrane hyperpolarization, and thus inhibitory synaptic transmission (1)(2)(3). The low [Cl − ] i that makes fast GABA A Rmediated synaptic inhibition possible is maintained by the neuronspecific K + -Cl − cotransporter KCC2 (4), a member of the cationchloride cotransporter SLC12 gene family (5). KCC2 is essential for survival, as KCC2 knockout mice die immediately at birth due to respiratory failure (6).…”

mentioning

confidence: 99%

“…KCC2 is essential for survival, as KCC2 knockout mice die immediately at birth due to respiratory failure (6). In the adult nervous system, decreased KCC2 expression correlates with neuropathic pain, spasticity following spinal cord injury, and epileptic seizures (5,(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Ivakine

Acton

Mahadevan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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KCC2 is a neuron-specific K + -Cl − cotransporter that is essential for Cl − homeostasis and fast inhibitory synaptic transmission in the mature CNS. Despite the critical role of KCC2 in neurons, the mechanisms regulating its function are not understood. Here, we show that KCC2 is critically regulated by the single-pass transmembrane protein neuropilin and tolloid like-2 (Neto2). Neto2 is required to maintain the normal abundance of KCC2 and specifically associates with the active oligomeric form of the transporter. Loss of the Neto2:KCC2 interaction reduced KCC2-mediated Cl − extrusion, resulting in decreased synaptic inhibition in hippocampal neurons. that makes fast GABA A Rmediated synaptic inhibition possible is maintained by the neuronspecific K + -Cl − cotransporter KCC2 (4), a member of the cationchloride cotransporter SLC12 gene family (5). KCC2 is essential for survival, as KCC2 knockout mice die immediately at birth due to respiratory failure (6). In the adult nervous system, decreased KCC2 expression correlates with neuropathic pain, spasticity following spinal cord injury, and epileptic seizures (5, 7-11).Based on the critical importance of KCC2 in the brain, an understanding of the mechanisms that promote and maintain KCC2 expression and efficacy is essential for designing therapeutic strategies to treat neurological disorders characterized by KCC2 dysfunction and the subsequent loss of inhibitory synaptic transmission. A major limitation in the development of these strategies is a lack of understanding regarding the cellular mechanisms regulating KCC2. In particular, KCC2 interacting proteins required for KCC2 transport and function in the mature CNS have not been identified, which represents a large gap in our fundamental knowledge regarding neuronal Cl − regulation and inhibitory synaptic transmission.Here, we identify neuropilin and tolloid like-2 (Neto2) as a KCC2 interacting protein in vivo and demonstrate that this interaction is required for normal neuronal Cl − homeostasis. Neto2 is a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein abundantly expressed in neurons (12), which is important for proper neurological function (13). CUB domains are evolutionarily conserved protein domains (14) that participate in protein-protein interactions (15, 16). In the present study, we performed an unbiased proteomic screen and discovered that Neto2 interacts with KCC2. We elucidated the role of this association and characterized its importance in the normal neurophysiological function of KCC2. Because Neto proteins were previously identified as auxiliary subunits of ionotropic glutamate receptors, including kainate and NMDA receptors (17-21), this study further extends the role of the Neto proteins to inhibitory synapses. ResultsNeto2 and KCC2 Interact in Vivo. Recent reports have demonstrated that Neto2 and its homologous protein Neto1 have important functions at excitatory synapses. Neto1 interacts with both the N-methyl D-aspartate receptor (NMDAR) and kainate receptor comp...

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“…The temporal expression of KCC2 is regulated by a number of factors, including neuronal activity, GABA level, and brain-derived neurotrophic factor (Aguado et al, 2003;Fiumelli and Woodin, 2007;Ganguly et al, 2001). Moreover, the activity of NKCC1 and KCC2 has been shown to be regulated by various mechanisms, including phosphorylation, cell volume, and oligomerization of KCC2 (Blaesse et al, 2009;Payne et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

Levav-Rabkin

Melamed

Clarke

et al. 2009

Neuropsychopharmacol

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Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1-7 and P4-14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl À co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4-14 hippocampi and cerebral cortices. Analysis of the Ca 2 + binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4-14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4-14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs.

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Cation-Chloride Cotransporters and Neuronal Function

Cited by 715 publications

References 236 publications

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

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Cation-Chloride Cotransporters and Neuronal Function

Cited by 715 publications

References 236 publications

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Neto2 is a KCC2 interacting protein required for neuronal Cl − regulation in hippocampal neurons

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

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Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons